Optimizing prostate cancer therapy strategies 5th ESO-ESMO … · Disclosures –Eleni Efstathiou...
Transcript of Optimizing prostate cancer therapy strategies 5th ESO-ESMO … · Disclosures –Eleni Efstathiou...
Optimizing prostate cancer therapy strategies
Where do we stand in 2019
Eleni Efstathiou M.D., PhD.
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Disclosures – Eleni EfstathiouResearch Support/P.I.
Janssen, Sanofi-Genzyme, Astellas/Medivation, Innocrin,
Tracon
Employee NA
Consultant NA
Major Stockholder NA
Speakers Bureau NA
Honoraria Janssen, Sanofi-Genzyme,
Scientific Advisory BoardJanssen, Sanofi-Genzyme, Tolmar, Takeda, Astra Zeneca,
Bayer,
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“Novel”
Androgen signaling
inhibitionBone Targeting AgentsChemotherapy
Approved ‘systemic’ therapies by biologic domain in advanced Prostate Cancer
Immunotherapy
Abiraterone AcetateEnzalutamideApalutamide Daralutamide
DocetaxelCabazitaxel Sipuleucel T Radium-223
Treatment of Primary
A systemic therapy after all? 5t
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Is there a change in therapeutic landscape?
Approved Agents moved upfront
mCRPC, metastatic castration-resistant prostate cancer;
mHSPC, metastatic hormone-sensitive prostate cancer;
nmCRPC, non-metastatic castration-resistant prostate cancer.
Hong JH, Kim IY. Korean J Urol. 2014;55:153-60.
Mottet N, et al. EAU/ESTRO/ESUR/SIOG Guidelines on Prostate Cancer 2017.
Available from: http://uroweb.org/guideline/prostate-cancer. Accessed February 2018.
Adapted from: Scher HI, et al. J Clin Oncol. 2016;34:1402-18.
Localised or locally
advanced prostate
cancer
Biochemical
recurrence
nmCRPC
Primary progressive
mHSPC
Newly diagnosed
mHSPC
mCRPCTerminal disease
(death)
First prostate cancer diagnosis
Non-metastatic
Metastatic castration resistant
Metastatic hormone sensitive
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Is Earlier Treatment Better ?
Sure … but what is the target ?
In majority of cases the Androgen Signaling Axis
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Enriched Genomic Alteration landscape in far advanced disease too late for Androgen
signaling inhibition and in the bigger picture for most targeting agents
Robinson D, et al. Cell. 2015;162:454
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Localised Disease: “limited” mutational landscape
TCGA Cell 2015
Would targeting earlier limit the variables and resistance ?
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Increase in mutation frequency and copy number alteration associated with
more advanced stage: in other words choose wisely ..?
Abida et al JCO Precision Oncology 2018 5t
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Tackling newly diagnosed metastatic prostate cancer
mCRPC, metastatic castration-resistant prostate cancer;
mHSPC, metastatic hormone-sensitive prostate cancer;
nmCRPC, non-metastatic castration-resistant prostate cancer.
Hong JH, Kim IY. Korean J Urol. 2014;55:153-60.
Mottet N, et al. EAU/ESTRO/ESUR/SIOG Guidelines on Prostate Cancer 2017.
Available from: http://uroweb.org/guideline/prostate-cancer. Accessed February 2018.
Adapted from: Scher HI, et al. J Clin Oncol. 2016;34:1402-18.
Localised or locally
advanced prostate
cancer
Biochemical
recurrence
nmCRPC
Primary progressive
mHSPC
Newly diagnosed
mHSPC
mCRPCTerminal disease
(death)
First prostate cancer diagnosis
Non-metastatic
Metastatic castration resistant
Metastatic hormone sensitive
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ADT + Docetaxel Overall Survival benefit in mHNPC
HR, hazard ratio.
1. Gravis G, et al. Eur Urol. 2016;70:256-62.
2. Kyriakopoulos CE, et al. J Clin Oncol. 2018;36:1080-7.
GETUG AFU-151 CHAARTED2
OS
(p
rop
ort
ion
)
1.0
0.8
0.4
0.2
0
0.6
0.9
0.7
0.3
0.1
0.5
Follow-up (years)
1 2 3 4 60 5 87
175
171
145
148
119
116
102
94
72
61
192
193
87
76
32
33
No. of patients at risk:
ADT + Doc
ADT alone
Median OS (months)
ADT: 48.6 (40.9–60.6)
ADT + Doc: 62.1 (49.5–73.7)
HR (95% CI): 0.88 (0.68–1.14);
p = 0.3
ADT + Doc
ADT alone
366
352
314
278
245
198
155
126
28
21
397
393
67
45
7
2
2
0
0
0
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Attempt 3 : STAMPEDE
James et al Lancet 2015
Patient Population mHNPC or HNPC N+Localized high risk PCawith plan to radiate
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STAMPEDE ADT + Docetaxel Survival benefit in mHNPC
James ND, et al. Lancet. 2016;387:1163-77.
1.0
0.8
0.4
0.2
0
0.6
OS
(%
)
Time from randomisation (months)
12 24 36 48 720 60
SOC
SOC + Doc
STAMPEDE: M1 disease
362 326 250 155 91 38 25
724 646 474 262 137 60 26
STAMPEDE: all patients
SOC, standard of care.
100
80
40
20
0
60
OS
(%
)
12 24 36 48 720 60 84
1093
545
876
447
538
290
322
181
87
51
1,184
592
166
93
43
20
(73)
(33)
(134)
(52)
(92)
(35)
(60)
(22)
(17)
(13)
(35)
(12)
(2)
(6)
SOC by Kaplan-Meier
SOC by flexible parametric model
SOC + Doc by Kaplan-Meier
SOC + Doc by flexible parametric model
No. of patients at risk (events)
SOC + Doc
SOC
Time from randomisation (months)
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Is ADT + Doc effective in “low-volume” mHNPC?
Kyriakopoulos CE, et al. J Clin Oncol. 2018;36:1080-7.
Kaplan-Meier estimates of OS for total patient population.
NR, not reached.
High-volume mHSPC Low-volume mHSPC
A uniform effect was noted for ADT + Doc in the STAMPEDE study
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ADT + Abiraterone Overall Survival benefit in mHNPC
1. Fizazi K, et al. N Engl J Med. 2017;377:352-60.
2. James ND, et al. N Engl J Med. 2017;377:338-51.CI, confidence interval; mHSPC, metastatic hormone-sensitive prostate cancer; OS, overall survival.
STAMPEDE2LATITUDE1
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Chi et al ASCO GU 2019
LATITUDE Final Analysis: Overall Survival
(median follow up 52 months)
• Median OS for patients receiving ADT + AA+P reached 4.5 years, 16.8 months longer than ADT+ placebos
0 6 12 18 24 30 36 42 48 54 60 66
Months
0
20
40
60
80
100
Ove
rall
su
rviv
al (%
)ADT + AA + P, 53.3 mo
ADT + placebos, 36.5 moNo. of events:
ADT + AA + P: 275 (46%)
ADT + placebos: 343 (57%)
HR 0.66 (95% CI: 0.560.78)
P<0.0001
Median treatment exposure:
ADT + AA + P: 25.8 mo
ADT + placebos: 14.4 mo
597 565 529 479 425 389 351 311 240 124 40 0
602 564 505 432 368 315 256 220 165 69 23 0
No. at risk
ADT + AA + P
ADT + placebos
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HOW DID PATIENTS FARE BASED ON RISK AND VOLUME IN
STAMPEDE ( ABIRATERONE+ADT VS ADT)
Pt No Median F/U
(mo)
HR
LATITUDE M1
“high risk”
1199 30.4 0.62 (0.51-0.76)
STAMPEDE AAP
M0+M1
1917 40 0.63 (0.52-0.76)
STAMPEDE AAP
(M1)
1002 40 0.61 (0.49-0.75)
STAMPEDE AAP
(M0)
915 40 0.75 (0.48-1.18)
Definition
CHAARTED
(volume)
High Visceral metastases
AND/OR
≥4 Bone metastasis
(≥1 outside vertebral column or spine)
LATITUDE
(risk)
High ≥2 high risk features
• ≥3 Bone metastasis
• Visceral metastasis
• ≥Gleason 8
What do we mean by ”Risk” or “Volume?”
Parker et al ESMO 2018 5t
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Population Number %
LATITUDE Low 428 47.5
LATITUDE High 473 52.5
CHAARTED Low 402 44.6
CHAARTED High 499 55.4
Individual CHAARTED Low
CHAARTED High
LATITUDE Low 333 (37%) 95 (10.5%)
LATITUDE High 69 (7.7) 404 (44.8)
STAMPEDE (ABIRATERONE / ADT )
SUBGROUP RISK/VOLUME DISTRIBUTION
N:942
18.2% NON OVERLAPPING
Parker et al ESMO 2018 5t
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RESULTS: LATITUDE RISK STRATIFICATION
EQUIVALENT PERFORMANCE
ADT + Abiraterone + Prednisolone (AAP) ADT alone Parker et al ESMO 2018 5t
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CHAARTED VOLUME CRITERIA: EQUIVALENT PERFORMANCE
ADT + Abiraterone + Prednisolone (AAP) better
ADT alone better Parker et al ESMO 2018
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Both treatment options show improvements in HRQoL over ADT
alone
1. Chi KN, et al. Lancet Oncol. 2018:19;194-206.
2. Patrick-Miller L, et al. J Clin Oncol. 2016;34:(Suppl 2S): abstract 286. FACT-P, Functional Assessment of Cancer Therapy–Prostate; HRQoL, health-related quality of life.
LATITUDE
ADT vs ADT + AAP1
CHAARTED
ADT vs ADT + Doc2
120
118
116
114
FA
CT
-P t
ota
l
3 60 9 12
Time (months)
ADT +
AAPADT
ADT +
AAPADT
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AEs: grade 3–5, n (%)ADT
(n = 1,184)
ADT + Doc
(n = 592)
Any 所有 399 (32) 288 (52)
Febrile neutropenia
发热性中性粒细胞减少15 (1) 84 (15)
Neutropenia
中性粒细胞减少6 (< 1) 66 (12)
GI disorders 消化道反应 36 (3) 45 (8)
Respiratory disorders
呼吸系统疾病27 (2) 29 (5)
Adverse Events between Abiraterone and Docetaxel
AEs: grade 3–5, n (%)ADT
(n = 960)
ADT + AAP
(n = 948)
Any 所有 315 (33) 443 (47)
Cardiovascular disorders 心血管疾病 41 (4) 92 (10)
Hypertension 高血压 13 (1) 44 (5)
Cardiac dysrhythmia 心律失常 2 (< 1) 14 (1)
Hepatic disorders 肝脏疾病 12 (1) 70 (7)
Increased ALT level ALT升高 4 (< 1) 53 (6)
Respiratory disorders 呼吸系统疾病 23 (2) 44 (5)
Laboratory abnormalities 实验室指标异常 21 (2) 34 (4)
STAMPEDE
ADT vs ADT + AAP1
STAMPEDE
ADT vs ADT + Doc2
1. James ND, et al. N Engl J Med. 2017;377:338-51.
2. James ND, et al. Lancet. 2016;387:1163-77.
aOnly AEs that differ by > 2% in the STAMPEDE trial (AAP and Doc arms) are shown.
AE, adverse event; ALT, alanine transaminase; GI, gastrointestinal.
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Strong evidence favouring AA+P
Toxicity profiles quite different and well known
Weak evidence favouring AA+P
No good evidence of a difference
FavoursADT+AA+P
FavoursADT+DOC
Hazard ratio
Metastatic progression-free
survival
Progression-free survival
Failure-free survival
Symptomatic skeletal events
Cause-specific survival
Overall survival
Head-to-head data in 566 pts (Nov-2011 to Mar-2013)
Proportionately different time spent in each disease state
No Difference in Survival in HNPC with use of Docetaxel or Abiraterone
AA+P = abiraterone acetate plus prednisone/prednisolone; ADT = androgen-deprivation therapy; DOC = docetaxel
Adapted from: Sydes M, et al. Abstract LBA31 presented at ESMO 2017Sydes et al Annals of Oncology 20185t
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STAMPEDE Subsequent Treatments:
Frequent use of Docetaxel post AA
limited use of drugs on ADT arm
James et al NEJM 20175th
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Sequencing and Accessing
Is it then matter of sequence or equally so of access ?
Availability
“window of opportunity”
Patient vulnerability / frailty
To what extent can biology guide us in determining sequence a priori ?
Making the most of heterogeneity / classification
Overlapping activity ?
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Would there be a preference of docetaxel over abiraterone ?
Docetaxel Preference
Low cost – Shorter duration
Disease that has aggressive features
High volume disease and specifically visceral disease?
Young men (early 50s) regardless of volume of disease ?
Window of concern in cases with constitutional symptomatology ?
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NCCN: “CAB provides modest to no benefit over castration alone in patients with
metastatic disease.”
ASCO: Antiandrogens (eg, bicalutamide, flutamide, nilutamide) may be offered,
accompanied by discussion of limited known clinical benefit”
EAU: ”CAB using non-steroidal anti-androgen (NSAA) appears to provide a small
survival advantage (<5%) vs. monotherapy (surgical castration or LHRH agonists)
beyond 5 years. However, some of the larger trials included in these reviews were
methodologically flawed and it is unlikely that this small advantage, if any, is useful in
daily clinical practice.”
NICE:” Do not offer CAB as a first line treatment for men with metastatic prostate
cancer”
Combined Androgen Blockade (CAB) in mHNPC
NCCN guidelines version3, 2016Basch et al. J. Clin. Oncol. 2014 32(30): 3436-3448https://pathways.nice.org.uk/ Mottet N, et al. EAU guidelines. https://uroweb.org/guideline/prostate-cancer/. Accessed June 13, 20165t
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Phase II evidence with older compounds only PSA response
PSA > 50%
Bicalutamide addition/withdrawal 15 - 33%1
Antiandrogen change 24 %2
Estramustinphosphate 20 %
Aminogluthetimid (+HC) 49 %3
Ketokonazole (+HC) 62 %4
Estrogens 80 %5
1Small, JCO 1997; 2Scher, JCO 1997; 3Sartor JNCI 1994;4Small, J Urol 1997, 5Orlando Ann Oncol 2000
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ARE THERE MEN WHO ARE BETTER OFF WITH ADT ALONE
Maybe Older men ? DATA FAVOR ABIRATERONE
SIOG analyses reveal that geriatric patients have more aggressive disease
They should be treated based on the presence of comorbidities :
hence the only clear contraindication is heart failure
Maybe older men with low metastatic volume : AGAIN DATA FAVOR ABIRATERONE
This analysis supports use of Abiraterone in low metastatic volume
Importantly significant early on impact Skeletal related events !
(Extrapolate better QOL)
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IS THE ADDITION OF ABIRATERONE TO ADT DETRIMENTAL ?
1 ADT alone causes known Adverse events that are sometimes overlooked including :
Short Term : Arterial hypertension, Metabolic Syndrome exacerbation ( weight gain, diabetes/ prediabetes,
hyperlipidemia), Emotional, AST/ ALT elevation, Hot flashes, fatigue.
Mid/ long term : bone loss, sarcopenia, cognitive decline ( mainly memory in subset)
Abiraterone Addition – may increase frequency and severity of events
Only added clinical risk :Hypokalemia ( a lot of older men on diuretics)
2 Only clear contraindication is Heart failure with low EF
3 Familiarity with Abiraterone has the risk of reduced monitoring
Conclusion : Patients on any hormonal manipulation need monitoring and good internal medicine support
Addition of Abiraterone does not significantly exacerbate events
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Time since registration(months)
Pro
babi
lity
of P
SA
-rel
apse
free
0.0
0.2
0.4
0.6
0.8
1.0
0 12 24 36 48
LHRH alone (70/98)LHRH+AA+Pred (58/99)
p-value=0.007
Efforts Underway: Intermittent Advanced
Androgen Signaling inhibition in M0 HNPC
Hazard Ratio 0.62(95% CI 0.44-0.88)
Efstathiou et al ASCO 2018
Link “driver biology” to outcomes by characterizing primary cancers
Extend findings to propose a risk stratified, marker based, adjuvant therapy in men at risk for recurrence following surgery
No diffencein time to eugonad state
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Residual Tumor following neoadjuvant abiraterone
for high risk prostate cancer AA+LHRHa LHRHa
Tumor Cell Density (%)
P < 0.0001 P < 0.0001
Tumor Epithelium Volume: Tumor Cell Density × Volume Tumor Volume (cc)
5
4
3
2
1
0
80
60
40
20
0
6
4
2
0
P = 0.003
Tumor Quantification measures associates with biochemical recurrence ( p < 0.001)superior to association of pathology stage with outcome (p< 0.001)
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How can data on EBRT on low volume disease change our practice with regard to abiraterone ?
MAYBE A COMBINATORIAL STRATEGY OPPORTUNITY
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MRC CTU at UCL
STAMPEDE: Radiotherapy to the primary in newly diagnosed mHNPC
Though not positive for unselected patients Clearly positive for the prespecified subset analysis of
Low metastatic burden
Aka a treatment with bone scan as a ‘predictor’ of outcome
Parker et al Lancet 20185t
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Overall survival: exploratory consistency analyses by baseline features
Is docetaxel planned as part of SOC?
Gleason sum score
Nodal status
Tumour status
WHO PS 0 vs 1-2
Age at randomisation
Subgroup
Overall
Docetaxel
No docetaxel
8-10
<=7
N+
N0
T4
T3
T2
<T2
1-2
0
70 or over
Under 70
Dths/N
SOC-only
34/182
357/844
332/818
41/173
251/617
118/345
126/260
200/583
33/84
5/12
120/297
271/729
168/433
223/593
Dths/N
SOC+RT
28/182
342/847
303/807
54/172
228/618
116/343
104/246
201/600
33/89
5/14
118/297
252/732
142/435
228/594
p-value
Interaction
0.63
0.084
0.47
0.66
0.87
0.066
(95% CI)
Haz. Ratio
0.92 (0.80, 1.06)
0.81 (0.49, 1.34)
0.93 (0.80, 1.08)
0.91 (0.78, 1.06)
1.34 (0.89, 2.02)
0.87 (0.72, 1.04)
0.97 (0.75, 1.25)
0.78 (0.60, 1.02)
0.97 (0.80, 1.18)
0.75 (0.44, 1.27)
0.61 (0.13, 2.82)
0.94 (0.73, 1.21)
0.92 (0.77, 1.09)
0.78 (0.63, 0.98)
1.03 (0.86, 1.24)
Favours: SOC+RT SOC-only
.5 .6 .7 .8 .9 1 1.2 1.4
SOC vs SOC+RT
No data on combination
With AA
However Synergy
anticipated
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Confirmation of tissue based driven observations
Bova et al Nature 20165th
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Will anticipated data
impact tailoring treatment
to the patient
even further?
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Triplet vs doublet treatment
BIC, bicalutamide; ENZA, enzalutamide; rPFS, radiographic PFS; SWOG, Southwest Oncology Group.
Study Identifier Arms Patients (N)Primary
endpoint
Status
LATITUDE NCT01715285 ADT ± AA 1,209 rPFS, OS Ongoing
STAMPEDE (Arm G) NCT00268476 ADT ± AA 1,800 OS Ongoing
PEACE-1 NCT01957436
ADT ± Doc vsADT + AA ± Doc
(± local RT)916 PFS, OS Recruiting
STAMPEDE (Arm J) NCT00268476 ADT ± AA + ENZA 1,800 OS Ongoing
SWOG-1216 NCT01809691 ADT + TAK-700 vs
ADT + BIC 1,304 OS Recruiting
ENZAMET NCT02446405 ADT + ENZA vs
ADT + antiandrogen1,100 OS Ongoing
TITAN NCT02489318 ADT ± APA 1,000 rPFS, OS Ongoing
ARCHES NCT02677896 ADT ± ENZA 1,100 rPFS Ongoing
ARASENS NCT02799602 ADT + Doc ± ODM-201 1,300 OS Ongoing
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Therapy development in prostate cancer
Earlier treatment merits and risks
Biology of disease Cumulative Adverse Events
Optimizing therapeutic strategies : short / mid /long-term treatment continuum
Novel targets and drug development how can / when will it affect patient care ?
The multifactorial role of the ‘host’
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When did nmCRPC become a “hot topic”
mCRPC, metastatic castration-resistant prostate cancer;
mHSPC, metastatic hormone-sensitive prostate cancer;
nmCRPC, non-metastatic castration-resistant prostate cancer.
Hong JH, Kim IY. Korean J Urol. 2014;55:153-60.
Mottet N, et al. EAU/ESTRO/ESUR/SIOG Guidelines on Prostate Cancer 2017.
Available from: http://uroweb.org/guideline/prostate-cancer. Accessed February 2018.
Adapted from: Scher HI, et al. J Clin Oncol. 2016;34:1402-18.
Localised or locally
advanced prostate
cancer
Biochemical
recurrence
nmCRPC
Primary progressive
mHSPC
Newly diagnosed
mHSPC
mCRPCTerminal disease
(death)
First prostate cancer diagnosis
Non-metastatic
Metastatic castration resistant
Metastatic hormone sensitive
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Definition of CRPC
Mottet N, et al. EAU/ESTRO/ESUR/SIOG Guidelines on Prostate Cancer 2018. Available
from: http://uroweb.org/guideline/prostate-cancer. Accessed February 2019.
Castrate serum testosterone <50 ng/dL or 1.7
nmol/L
AND EITHER
Biochemical progression
3 consecutive rises of PSA
with PSA >2 ng/mL
Radiological progression
Appearance of ≥2 bone
lesions on bone scan or
enlargement of soft tissue
lesion
(RECIST criteria)
OR
Based on conventional bone scan and CT Scan
Trivia question:
Which country approved novel androgen signalling inhibitors for all CRPC as a first indication? 5t
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1. Moreira DM, et al. Urology. 2016;96:171-6.
2. Smith MR, et al. J Clin Oncol. 2005;23:2918-25. 3. Smith MR, et al. Cancer. 2011;117:2077-85.
4. Freedland SJ, et al. J Clin Oncol. 2007;25:1765-71. 5. Smith MR, et al. J Clin Oncol. 2013;31:3800-6.
nmCRPC, non-metastatic castration-resistant prostate cancer;
PSADT, prostate specific antigen doubling time.
PSADT as a measure of progression in the
nmCRPC
• Patients with M0 CRPC will invariably
develop detectable metastases
• Rapidly rising PSA in these patients is
linked to risk of:1-4
Metastasis
Locoregional disease progression
and symptom development
Morbidity
Limited survival
PSADT (months)
Re
lati
ve r
isk
for
bo
ne
m
eta
stas
is o
r d
eat
h
Shorter PSADT
Inc
rea
sin
g r
isk
20 18 16 14 12 10 8 6 4 2
3.0
2.8
2.6
2.4
2.2
2.0
1.8
1.6
1.4
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Androgen signaling inhibition in nmCRPC:
Does it work ?
1. Smith MR, et al. N Engl J Med. 2018;378:1408-18.
2. Hussain M, et al. N Engl J Med. 2018;378:2465-74.
3. Fizazi K, et al. N Engl J Med. 2019;doi: 10.1056/NEJMoa1815761
Apalutamide Enzalutamide Darolutamide
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Trial Design: All basically identical
1. Smith MR, et al. N Engl J Med. 2018;378:1408-18.
2. Hussain M, et al. N Engl J Med. 2018;378:2465-74.
3. Fizazi K, et al. N Engl J Med. 2019;doi: 10.1056/NEJMoa1815761
Eligibility• nmCRPC
• PSADT ≤ 10 months
• Baseline PSA ≥ 2 ng/L
On-study requirement• Continuous ADT
Stratification• PSADT < 6 or 6–10 months
• Bone-targeted agent use: yes/no
Treatment + ADT
PBO + ADT
2:1
Primary endpoint:
Metastases Free Survival (MFS)
Key Secondary endpoints:
Overall Survival, Time to PSA
Progression, Quality of Life
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NCT01946204PSADT, prostate-specific antigen doubling time; ADT, androgen deprivation therapy; APA, apalutamide; QD, daily; PBO, placebo; MFS, metastasis-free survival; Rx, treatment; MD, medical doctor; ABI/PRED, abiraterone acetate plus prednisone; PFS2, second progression-free survival.
Eligibility• nmCRPC
- Pelvic nodes <2 cm below iliac bifurcation (N1) allowed
• PSADT ≤10 months
On-Study Requirement• Continuous ADT
Stratifications• PSADT >6 mo or ≤6 mo• Bone-sparing agents, y/n• N0 or N1
Second Rx at MD’s
discretion, including
open-label ABI/PRED
APA 240 mg QD
+ ADT(n = 806)
PBO +
ADT(n = 401)
Randomization
MFS
PROGRESSION
2nd progression-free survival
(PFS2)
MFS(primary end point)
Ongoing PBO patients crossover to APA after unblinding
2:1(N = 1,207)
SPARTAN ─ Overall Study Design Phase 3 Placebo-controlled, Randomized International Study
45
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MFS PBO APA
Median time to event, mo 16.2 40.5
HR, 0.28 (95% CI, 0.23-0.35),
P value <0.0001
Time to Symptomatic Progression PBO APA
Median time to event, mo Not reached Not reached
HR, 0.45 (95% CI, 0.32-0.63),
P value <0.0001
Time to PSA Progression PBO APA
Median time to event, mo 3.7 Not reached
HR, 0.06 (95% CI, 0.05-0.08),
P value <0.0001
APAPBO
APA
PBO
806
0
20
40
60
80
100
Meta
sta
sis
-free S
urviv
al (%
)
MonthsNo. at risk
713 652 514 398 282 180 96 36 16 3 0
401 291 220 153 91 58 34 13 5 1 0 0
0 4 8 12 16 2420 28 32 36 40 44
Primary End Point:MFS72% risk reduction of distant progression or death
PSA, prostate-specific antigen; HR, hazard ratio; CI, confidence interval; SRE, skeletal-related event; sx, symptoms.
Secondary End Point:Time to Symptomatic Progression55% risk reduction of SRE pain progression/worsening sx, clinically significant sx requiring intervention
APA
PBO
0 4 8 12 16 20 24 28 32 36 40 44
806 769 732 601 478 344 226 127 49 19 4 0
401 373 344 270 206 152 96 45 17 7 0 0
Pati
en
ts W
ith
ou
t S
ym
pto
mati
c P
rog
ressio
n (
%)
0
20
40
60
80
100
Months
APA
PBO
No. at risk
Exploratory End Point:Time to PSA Progression94% risk reduction in PSA progression
APAPBO
806 695 597 435 306 215 128 69 29 2 0
401 139 50 14 8 4 0 0 0 0 0 0
11
Pati
en
ts W
ith
ou
t P
SA
Prog
ressio
n (
%)
0
20
40
60
80
100
0 4 8 12 16 20 24 28 32 36 40 44
Months
APA
PBO
No. at risk
SPARTAN Results: APA Significantly Prolonged MFS, Time to Symptomatic
Progression, and Time to PSA Progression
46
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47
Objective• Report the updated SPARTAN PFS2 exploratory end point and safety data after 1 year of
additional follow-up using cumulative data.
• PFS2 is defined as the time from randomization to disease progression on subsequent
anticancer therapy, or death.All men on placebo
Were given
apalutamide
or abiraterone
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Median time to PFS2 was not reached (APA) versus 39.3 months (PBO)
50% reduction in the risk of disease progression over two lines of anticancer therapy or death in favor of APA
Pa
tie
nts
Wit
ho
ut
Se
co
nd
ary
Pro
gre
ss
ion
or
Dea
th
Time From Randomization (Months)
0 4 528 12 16 20 24 28 32 36 40 44 48
HR, 0.5 (95% CI, 0.39-0.63)
P <0.0001
100
80
60
40
20
0
806 779 760 730 693 637 525 398 289 191 117 44 13 0
401 386 362 331 285 243 182 124 75 45 26 9 1 0
No. at risk
APA
PBO
PBO, 39.3 mo
(median)
APA, not reached
Apalutamide Shows Continued Benefit on PFS2
48
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Why is mCRPC lagging behind these past few years ?
mCRPC, metastatic castration-resistant prostate cancer;
mHSPC, metastatic hormone-sensitive prostate cancer;
nmCRPC, non-metastatic castration-resistant prostate cancer.
Hong JH, Kim IY. Korean J Urol. 2014;55:153-60.
Mottet N, et al. EAU/ESTRO/ESUR/SIOG Guidelines on Prostate Cancer 2017.
Available from: http://uroweb.org/guideline/prostate-cancer. Accessed February 2018.
Adapted from: Scher HI, et al. J Clin Oncol. 2016;34:1402-18.
Localised or locally
advanced prostate
cancer
Biochemical
recurrence
nmCRPC
Primary progressive
mHSPC
Newly diagnosed
mHSPC
mCRPCTerminal disease
(death)
First prostate cancer diagnosis
Non-metastatic
Metastatic castration resistant
Metastatic hormone sensitive
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Advancement in mCRPC
1. Fizazi K, et al. N Engl J Med. 2017;377:352-60. 2. Sweeney CJ et al. N Engl J Med. 2015; 373:737-46.
3 Tannock IF, et al. N Engl J Med. 2004;351:1502-12. 4. Ryan CJ, et al. The Lancet. 2015;16:152-60. 6.
Beer TM, et al. N Engl J Med. 2014;371:424-33. 7. Scher HI et al. N Engl J Med 2012;367:1187-97. 8. de
Bono J, et al. Lancet. 2010;376:1147-54. 9. Parker C et al. Engl J Med 2013;369:213-23.
Study Agents N Indication HR ∆OS (mo)
TAX-3273 DOC/P vs
mitoxantrone /P1,006 mCRPC, symptomatic or not 0.76 +2.9
COU-AA-3024
ABI/P vs P 1,088mCRPC (pre-DOC), mild/no symptoms
No visceral mets0.81 +4.4
COU-AA-3015
ABI/P vs P 1,195 mCRPC (post-DOC) 0.74 +4.6
PREVAIL6
ENZ vs pbo 1,717 mCRPC (pre-DOC), mild/no symptoms 0.77 +4.0
AFFIRM7
ENZ vs pbo (or P) 1,199 mCRPC (post-DOC) 0.63 +4.8
TROPIC8 CABA/P vs mito/P 755 mCRPC (post-DOC) 0.70 +2.4
ALSYMPCA9 Radium-223 vs pbo 921 mCRPC (post-DOC or unfit for DOC) 0.70 +2.8
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Determines the efficacy of individual therapeutic
agents and thus leads to drug approval However
It does not inform impactful sequences or combinations
and strategy for their allocation over time to maximize
benefits !
“Drug Development Paradigm”
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Challenges
Patients treated on reported phase III randomized studies are
selected by “crude” prognostic criteria.
Patients treated as “one size fits all” ;
therefore selection of therapy by objective criteria or predictors
not enabled
The design of “practice changing” studies does not account
for interaction between “therapy domains”;
Thus sequences become empirical and combinations a concern.
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Time for Combinatorial Strategy ?
Still far removed from selecting specific tumor subsets
And focused on a one fits all approach
-We should keep in mind the negative track record
( ~15 negative docetaxel plus trials )
Enticing but with a lot of caveats if untested
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Chemo Based Combinatorial Trials
Quinn et al Annals of Onc 2018
And then there are the novel androgen
signaling inhibitor + trials…5th
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HERE’S HOW WE CAN EASILY FAIL:
ERA 223 (NCT02043678)
Bone health agents (denosumab or bisphosphonates) only permitted in patients receiving them at baseline; initiation during the study prohibited to prevent confounding effects.ALP, alkaline phosphatase; CRPC, castration-resistant prostate cancer; ECOG PS, Eastern Cooperative Oncology Group performance status; HRQoL, health-related quality of life; IV, intravenous; mCRPC, metastatic castration-resistant prostate cancer; OS, overall survival; PSA, prostate-specific antigen; rPFS, radiological progression-free survival; SSE-FS, symptomatic skeletal event-free survival.
Target
accrual
N=800Study population
• Patients with bone-predominant
mCRPC (≥2 bone metastases)
• Asymptomatic or mildly symptomatic
• ECOG PS of 0 or 1
• No prior chemotherapy for CRPC
• No known brain or visceral
metastases
1:1
Randomisation
Primary endpoint• SSE-FS
Secondary endpoints• OS
• rPFS
• Time to chemotherapy
• Time to opiate use for cancer
pain
• Safety
Exploratory endpoints• PSA response
• Time to PSA progression
• ALP response
• Time to ALP progression
• HRQoL
Abiraterone acetate 1000 mg qd and prednisone/prednisolone 5 mg bid (AAP) +
Radium-223 55 kBq/kg IV every 4 weeks for 6 cycles
Abiraterone acetate 1000 mg qd and prednisone/prednisolone 5 mg bid (AAP) +
Matching placebo
Stratification factors
• Geographical region
• Total ALP level at baseline (ALP <90 vs ≥90 U/L)
• Use of bone health agents
389 events were required to detect a 39%
increase in SSE-FS using a test with a 2-sided
alpha of 0.05, 90% power and 1:1 randomisation
Accrual dates 3/2014 – 8/2016
Smith et al ESMO 20185th
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Primary Endpoint not met …
SSE-FS
AAP +
radium-223
N=401
AAP +
placebo
N=405
Events, n (%) 196 (49) 190 (47)
Median (95% CI),
months
22.3
(20.4–24.8)
26.0
(21.8–28.3)
HR (95% CI) 1.122 (0.917–1.374)
P-value (2-sided) 0.2636
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45
401 380 355 310 272 245 202 126 78 44 25 12 7 6 1 0405 384 353 323 301 274 214 152 94 59 30 16 6 5 3 0
Number at risk
Sym
pto
matic S
kele
tal E
vent-
Fre
e S
urv
ival P
robabili
ty
AAP + radium-223AAP + placebo
Months Since Randomisation
TEAEs in ≥15% of patients in either group, n (%)AAP + radium-223
N=392
AAP + placebo
N=394
All Grade 3 Grade 4 All Grade 3 Grade 4
Fracture† 103 (26) 35 (9) 1 (0.3) 38 (10)* 12 (3) 0
Fracture Rate more than doubles with the combination
Smith et al ESMO 20185th
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Post-Hoc Subgroup Analysis of Fractures by Baseline
Bone Health Agent Use
AAP, abiraterone acetate and prednisone/prednisolone; BHA, bone health agent; NE, not estimable.
Patients with
≥1 fracture (%)
29
15
37
11
7
15
0
5
10
15
20
25
30
35
40
Overall population Patients with BHAs at baseline Patients without BHAs at baseline
AAP + placebo
AAP + radium-223
Smith et al ESMO 20185th
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Will PARP inhibitors change the landscape?
It all depends on the approach
Drug ClinicalTrials.gov ID Phase Primary endpoint
mCRPC (Phase 1/2)
Olaparib NCT01682772
NCT03263650
NCT01972217
NCT02893917
NCT03317392
NCT03012321
2
2 randomised
2 randomised
2 randomised
1/2 randomised
2 randomised
RR
PFS
rPFS
rPFS
(Phase 2) rPFS
PFS
Niraparib NCT02854436 2 ORR
Rucaparib NCT02952534
NCT03338790
2
2 randomised
ORR + PSA response
ORR + PSA response
Talazoparib NCT03148795 2 ORR
Veliparib NCT0157612 2 randomised PSA response
Drug ClinicalTrials.gov ID Phase Primary endpoint
mHSPC
Olaparib NCT03047135 2 PSA response
Rucaparib NCT03413995 2 PSA response
Drug ClinicalTrials.gov ID Phase Primary endpoint
mCRPC (Phase 3)
Olaparib NCT03263650 3 rPFS
Rucaparib NCT02975934 3 rPFS
Talazoparib NCT03395197 3 rPFS
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*Prednisone/prednisolone (5 mg) was administered alongside abiraterone as indicated. bid, twice daily; CTC, circulating tumor cell; HRRm, homologous recombination
repair gene mutation; mCRPC, metastatic castration-resistant prostate cancer; od, once daily; PCWG, Prostate Cancer Working Group; RECIST, Response Evaluation
Criteria in Solid Tumors; rPFS, radiographic progression-free survival
• mCRPC
• Prior treatment with
docetaxel for mCRPC
• ≤2 prior lines of
chemotherapy
• No prior 2nd-generation
antihormonal agents
Randomized 1:1
Double-blind
N~140
Olaparib tablets
300 mg bid
+
abiraterone*
1000 mg od
Placebo
+
abiraterone*
1000 mg od
Secondary endpoints:
• rPFS by HRRm status
• Time to second progression (PFS2)
• Overall survival (OS)
• Objective response rate (ORR)
• CTC-conversion rate
• Safety and tolerability
• Times to first and second subsequent
therapies (TFST/TSST)
• Health-related quality of life (HRQoL)
Primary endpoint:
• Radiologic progression-free survival
(investigator-assessed; RECIST 1.1, PCWG2)
Tre
atm
en
t u
ntil d
ise
ase
pro
gre
ssio
n
A Randomized Phase II Trial: Olaparib Combined With Abiraterone in
Patients With Metastatic Castration-Resistant Prostate Cancer
Clarke N, et al. Lancet Oncology 2018.5t
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Combinatorial Strategy report
Outcome independent of mutation status
0 3 6 9 12 15 18 21 24 27 30
1.0
0.8
0.6
0.4
0.2
0.0
Pro
po
rtio
n o
f p
ati
en
ts e
ve
nt-
fre
e
= 5.6
Time from randomisation (months)
Events, n (%)
K-M median, monthsOlaparib + AAP
(n = 71)
AAP
(n = 71)
46 (65)
13.8
54 (76)
8.2
HR 0.65
95% CI 0.44–0.97; p = 0.034
No. of patients at risk
Olaparib + AAP 71 58 50 42 33 26 21 18 13 8 0
AAP 71 48 39 25 21 19 16 14 10 7 0
Clarke N, et al. Lancet Oncology 2018.5t
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OLA + AAP: Safety is a very important consideration
Olaparib + AAP (n = 71) AAP (n = 71)
Nausea 27 15
Anaemia 22 1
Back pain 18 14
Constipation 18 8
Asthenia 16 10
Fatigue 15 9
Vomiting 15 9
Peripheral oedema 13 8
Decreased appetite 12 5
Diarrhoea 11 8
Cough 11 2
Serious cardiovascular AEs 7 1
Olaparib + AAP
Myocardial infarction, n = 4; fatal cardiac failure, n = 1;
chronic cardiac failure, n = 1; fatal ischaemic stroke, n = 1
AAP
Thrombotic stroke, n = 1
All grades
Grade ≥ 3
2
15
1
1
3
1
2
2
7
2
1
1
1
1
Clarke N, et al. Lancet Oncology 2018.5t
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Newly diagnosed
mHSPC
The Disease landscape and Therapy Development
mCRPC, metastatic castration-resistant prostate cancer;
mHSPC, metastatic hormone-sensitive prostate cancer;
nmCRPC, non-metastatic castration-resistant prostate cancer.
Hong JH, Kim IY. Korean J Urol. 2014;55:153-60.
Mottet N, et al. EAU/ESTRO/ESUR/SIOG Guidelines on Prostate Cancer 2017.
Available from: http://uroweb.org/guideline/prostate-cancer. Accessed February 2018.
Adapted from: Scher HI, et al. J Clin Oncol. 2016;34:1402-18.
High risk Localised
prostate cancerBiochemical
recurrence
nmCRPC
Primary
progressive
mHSPC
mCRPCEnd Stage
disease
Intermediate Risk
prostate cancer
Unmet Need
Currently Addressed
Primary field of drug
development
First prostate cancer diagnosis
Non-metastatic
Metastatic castration resistant
Metastatic hormone sensitive
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Making the most of data
Our clinical decisions do not fit a ‘linear model’ and are the result of
‘multivariate’ considerations informed by details
It s tougher to treat patients outside trials
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Trying to be “Precise” in daily practice (2015)(2015)
80 yr old veteran ‘full of life’
Reached MDACC with a PSA of 8500 in a wheelchair with pending spinal cord compression
and weight loss, anemia, high ldh (PS:3)
Biopsy – GS 8 (4+4)
Started 240mg degarelix loading dose and lower T spine radiation (+steroids)
Improved to PS 1 and transitioned to LHRHa in 4 weeks
WHAT WOULD YOU CONSIDER ADDING ?
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How Would you treat gentleman ?
A. Add Docetaxel
B.Add Abiraterone Acetate
C.Add Bicalutamide
D.Continue Monitoring
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Primary Resistance to ADT within 3 months
8500
1800
3900
PS 2Diabetic Vascular disease lack of local social/ family support
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How would you treat gentleman ?
A. Add Docetaxel
B Add Abiraterone Acetate
C Add Bicalutamide
D Perform Imaging first
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Diagnosis Bone Scan (3/2015)
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Follow up Bone Scan (08/2015)
ALP had normalised and pain improved 5t
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Lymph node Disease Development
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How Would you treat gentleman ?
A. Add Docetaxel
B Add Abiraterone Acetate
C Add Bicalutamide
D Continue Monitoring
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Sustained Biochemical and Clinical Response
on Abiraterone Acetate
ADT initiation
ABI initiation PSA 3900
PSA 19PSA 3
Improvement PS 1 No need for opiatesPatient remains on treatment to Date
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Alkaline Phosphatase Kinetics
Do not be disturbed by Transient ALP elevation
ADT
ABI
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The 2019 Dilemma
A patient like Bruce if diagnosed today would have been
treated with abiraterone acetate +LHRHa in a US practice
… the question for all of us is :
What if Bruce was fit for both docetaxel and abiraterone ?
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Biomarker Driven Research for prime time?
Not so fast ..
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Hypothesis:
Integration biologic
understanding with clinical
context can lead to successful
treatment strategy.
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Paul: 82 yr old very fit and active, BMI 24
Urination frequency and unexplained loss of weight 10 kg in 2 ms .
No Pain
June 15 PSA 2.2– June 16 PSA 25
July 16 Mayo Clinic : de novo metastatic PCa GS 9 (5+4) High Volume
Bulky local disease + Bone mets
Recommendations : ADT + Docetaxel
( High Volume) ADT initiated
MDACC second opinion :
Octagenarian though fit and Asymptomatic
PSA dropped to 2 within a month
A need to acquire Knowledge to make most of information
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What would be your treatment plan
1. ADT + Monthly denosumab
2. ADT and PSA monitoring
3. ADT and imaging and PSA monitoring
4. ADT + docetaxel
5 .ADT + Abiraterone Acetate
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Foundation Sequencing Results
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Tracking Paul’s PSA
Jan 17
Primary Resistance to ADT within 6 ms
Though PSA had
dropped <1
08 /16 CTC : 0 , MRI of spine no epidural disease,
01/17 Rise in PSA to 2, CTC 1 Bone Scan Stable, MRI stable
PS 0 no new symptoms , urinary frequency better
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What would you advise ?
1. Add Chemo with docetaxel
2 Add Abiraterone
3. Stay the course given lack of imaging progression
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Paul’s life on Chemotherapy Feb 17
He received 5 cycles of chemotherapy reduced dose after 2nd
Neuropathy G2 , Fatigue G2 , Alopecia G2
Initial PSA drop but rise after C3
After C4 urinary frequency ensues
Decision to givea month break
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A month after chemo break (July 2017)
PSA 10 CTC 62
Neuropathy Fatigue Improved, Chemo related Anemia ongoingMRI/ CT assessment : Bone Disease remains controlled
Local Disease exhibiting progression in line with symptoms
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What is your recommendation
1. Continue Chemo but change to cabazitaxel plus carboplatin given mutational load
2 Seek local palliative treatment TURP+/- EBRT
3. Stop Chemo Initiate Abiraterone Acetate
4. Other ?
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Two months of AbirateronePaul Came to my clinic Sep 25 2017
Abiraterone Acetate
PS 0Symptoms ImprovedPSA: <1 CTC: to favorable from 62 to 2
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Make the most of data – adapt to your practice
Monitor patients diligently – details matter
Listen to the need of the patient
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MRC CTU at UCLPatients and their families
Philantropists and Funding AgenciesMr/Ms Stanford AlexanderMr R. Eckstein
Prostate Cancer FoundationMD Anderson Prostate Cancer SPOREDavid H. Koch Center Genitourinary Center FacultyUrology Brian Chapin John Davis John PapadopoulosLouis PistersCurtis PettawayJohn AraujoAna AparicioHirak BasuPaul CornChristopher J LogothetisSumit SubudhiMark TitusShi-ming TuJennifer WangAmado ZuritaBiostatisticsSijin Wen Xuemei Wang
Pathology Patricia TroncosoVictor OrtegaRadiology Tharak BathalaVikas KundraInvernentional RadiologyRahul ShethCancer Systems ImagingPratip BhattacharyaDaniel FrigoDavid Piwnika Worms Imaging PhysicsJames BanksonGenomic MedicineAndy FutrealLily Zhang
Clinical and Tissue Research LeadersIna ProkhorovaMichael ClemingsDoyle BosqueCherie PerezAlexander & Eckstein Laboratory TeamsLaisa Abraham Carol BlandonAnh Hoang Sherie Hodges
IT Development – PrometheusSergio GarzaCindy CarterLisa Pruitt
Research Team Myrto Boukovala MDNikolaos Spetsieris MDJustin Weldon
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